Nicotinic acid has been used for decades to reduce plasma cholesterol and triglycerides and raise HDL[unreadable] cholesterol levels, and has also been demonstrated to reduce risk of atherosclerotic cardiovascular disease.[unreadable] Recently, a receptor for nicotinic acid was discovered. Called HM74A (GPR109A), it is a G-protein coupled[unreadable] receptor that is part of a gene cluster of three highly homologous genes; the other two are known as HM74[unreadable] (GPR109B) and GPR81. While expression of HM74A is substantial in adipose tissue, we and others have[unreadable] found that HM74A is also expressed in activated macrophages and vascular cells. Thus the possibility that[unreadable] nicotinic acid may have direct pharmacologic effects, and endogenous ligands direct physiologic effects, on[unreadable] the vasculature is intriguing. In this Project we will address the role of HM74A activation by nicotinic acid in:[unreadable] 1) modulating adipocyte metabolic function, cholesterol efflux, and adipokine secretion; 2) modulating[unreadable] macrophage lipid metabolism, cholesterol efflux, and inflammatory response; 3) modulating the vascular[unreadable] response to vascular injury and atherosclerosis; 4) the genetics and pharmacogenetics of this receptor[unreadable] family. The present studies are designed to address these questions using cell biological, animal model, and[unreadable] human investigative studies. These studies relate directly to studies in Project by FitzGerald by studying the[unreadable] interaction of HM74A with prostaglandin metabolism, specifically PGD2. They relate to Project by Reilly by[unreadable] focusing on the impact of HM74A in adipose tissue on vascular injury and by making use of two of the[unreadable] clinical studies organized and run through Project by Reilly. They make use of the Biomarker Core through the use[unreadable] of proteomic and lipidomic approaches to uncover novel pathways modulated by HM74A activation in[unreadable] different cell types. They utilize the Animal Model Core through a variety of vascular injury experiments in[unreadable] mice. These studies will advance our knowledge of the role of the nicotinic acid receptor HM74A in[unreadable] metabolism, inflammation, and vascular injury. The studies proposed here will fill in many of the knowledge[unreadable] gaps about nicotinic acid and its receptor with regard to cardiovascular disease, vascular injury, and the[unreadable] cutaneous flushing. As such, they will help to advance the science toward discovering better ways to target[unreadable] HM74A with the goal of reducing cardiovascular disease.